Journal article
Hepatocyte growth factor and Sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth
Cancer research (Chicago, Ill.), v 68(19), pp 7838-7845
01 Oct 2008
PMID: 18829539
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Medulloblastomas are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral neurologic injury. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas. Hepatocyte growth factor (HGF) and its cell surface receptor c-Met are highly expressed in human medulloblastomas, and elevated levels of c-Met and HGF mRNA predict an unfavorable prognosis for patients. HGF is neuroprotective for cerebellar granule cells and promotes growth of human medulloblastoma cells in culture and in murine xenografts. We modeled the ability of HGF to induce medulloblastomas in mice using a version of the RCAS/tv-a system that allows gene transfer to cerebellar neural progenitors during their postnatal expansion phase when these cells are highly susceptible to transformation. Here, we report a high frequency of medulloblastoma formation in mice after postnatal expression of HGF in cooperation with Shh. Some tumors showed neurocytic differentiation similar to that in human nodular medulloblastomas with activated Shh signaling. Systemic administration of a monoclonal antibody against HGF prolonged survival of mice bearing Shh + HGF-induced medulloblastomas by stimulating apoptosis. These findings indicate a role for HGF in medulloblastoma initiation and growth and show efficacy of HGF-targeted therapy in a mouse model of endogenously arising tumors.
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Details
- Title
- Hepatocyte growth factor and Sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth
- Creators
- Mandy J. Binning - University of UtahToba Niazi - University of UtahCarolyn A. Pedone - University of UtahBachchu Lal - Neurology, IncCharles G. Eberhart - College Station Medical CenterK. Jin Kim - Galaxy BiotechJohn Laterra - Neurology, IncDaniel W. Fults - University of Utah
- Publication Details
- Cancer research (Chicago, Ill.), v 68(19), pp 7838-7845
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 8
- Grant note
- R01NS043987 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01CA108622 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA108622; NS43987; CA129192 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000260029900019
- Scopus ID
- 2-s2.0-54249163448
- Other Identifier
- 991021918103704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology